A vaccine is urgently needed to stop the HIV pandemic. The failed STEP/Phambili trial of the Merck vaccine and the unexpected results that the vaccine may have potentially enhanced susceptibility to HIV infection indicates that we do not understand the nature of protective anti-HIV immunity. Although CD8+ T cell responses are clearly associated with control of viral replication in HIV and SIV infection (reviewed in (Walker and Burton, 2008), there are also examples of uncontrolled viral replication in the face of strong effective CD8+ T cell responses (Abel et al., 2004a; Genesca et al., 2007a; Genesca et al., 2007b; Mueller et al., 2008; Staprans et al., 2004). In all these cases, immune activation and inflammation-driven viral replication cannot be contained despite strong anti-viral CD8+ T cell responses. Thus innate/inflammatory responses might be extremely important in eliciting immune activation that drives early virus replication in the local mucosal tissues (Cecchinato et al., 2008). Thus adaptive CD8+ T cell memory responses that could otherwise effectively control virus replication cannot in an environment with hogh levels of immune actovation.. Thus, we will determine if there is an association between innate immune responses and outcome of mucosal SIV challenge in rAdSSIV vaccinated monkeys by analyzing innate anti-viraleffector mechanisms, T cell activation levels and the inflammatory environment in blood, mucosal surfaces, and in lymphoid tissues. We will focus on the role of type I interferons, the role of innate effector cells with cytotoxic activity, and the influence of innate responses on immune activation, regulation and inflammation. The balance between innate immune responses, immune activation and adaptive antiviral immunity may be critical in determining the outcome of repeated mucosal HIV exposure. Thus, the experiments we propose in this Project will define the level and extent of innate immunity and immune activation. The immune activation/innate immunity studies proposed here are novel and important in understanding potential correlates of HIV vaccine-mediated protection or failure that have been poorly considered to date. RELEVANCE (See instructions): If we can identify innate immune mechanisms important in vaccine-mediated protection against, or enhanced susceptibility to, mucosal SIV challenge, then we can then try to exploit or avoid these responses with future HIV vaccine strategies.